Deguelin induces PUMA-mediated apoptosis and promotes sensitivity of lung cancer cells (LCCs) to doxorubicin (Dox)

As a natural agent for chemotherapy, deguelin remarkably suppresses proliferation in numerous solid cancers. Nevertheless, the molecular mechanisms of its suppression are still insufficient. In our research, it was revealed that deguelin induced cell death of lung cancer cells (LCCs) by triggering expression of PUMA. Deguelin triggered PUMA induction independently of p53 via suppression of PI3K/AKT pathway, therefore stimulating Foxo3a to bind with PUMA promoter and stimulate its transcription. Subsequent to activation, PUMA motivated Bax as well as the intrinsic mitochondrial cell death pathway. Removal of PUMA from LCC cells led to deguelin resistance, suggesting deguelin-induced cell death was modulated by PUMA. Furthermore, we demonstrated that deguelin enhanced the chemotherapeutic sensitivity of doxorubicin in vitro and in vivo, which were associated with potentiated PUMA induction. Taken together, these results establish a critical role of PUMA in mediating the anticancer effects of deguelin in lung cancer cells and provide the rationale for clinical evaluation.